NCI Provocative Question #2: ?How do variations in immune function caused by comorbidities or observed among different populations affect response to cancer therapy?? The success of checkpoint blockade immunotherapy and its role in the future of cancer treatment is now beyond debate, but durable responses still only occur in a subset of patients. Extending the success of immunotherapy to a broader range of patients requires new insight into the variables that dictate therapeutic success and failure. More than a third of Americans are now considered obese, a condition associated with impaired immune responses to infections and vaccines, and a greater risk of developing some types of cancer. This implies a potential link between obesity and poor tumor immunity, which has been documented in a few preclinical studies but mechanistic insight remains sparse. More importantly, efforts to understand how obesity influences outcomes in human cancer patients has been mired by conflicting results and limited metrics such as body mass index (BMI) to measure obesity in people. These inconsistencies have contributed to the controversial ?obesity paradox?, which suggests that obesity has a positive impact on outcomes for patients with cancer, cardiovascular disease or a host of other ailments, but this idea is facing mounting skepticism. Our preliminary research in a mouse tumor model refutes the obesity paradox, identifying obesity as a barrier to the success of cancer immunotherapy. Here, obesity was associated with poor control of melanoma tumor growth following checkpoint blockade immunotherapy, associated with dysfunction of tumor infiltrating T cells. We hypothesize that obesity-related comorbidities such as excessive adipose tissue, inflammation, altered metabolism and liver function compromise immunotherapy by suppressing the functional restoration of T cells. To test this, we will employ several innovative mouse models that allow discrete manipulation of T cell effector pathways (Aim 1), excessive adiposity and the development of fatty liver disease (Aim 2). These mechanistic studies will enable the contributions of individual comorbidities to be rigorously dissected. We predict that results from these animal experiments will enable parallel discoveries in cancer patients (Aim 3), revealing the critical components of human obesity that influence outcomes during cancer immunotherapy. Our goal is to define the complex obesity-related factors that shape immune responses to cancer and influence outcomes during cancer immunotherapy. Given the magnitude of the obesity epidemic, our translational research has the potential to benefit a significant number of cancer patients for whom current immunotherapies may have limited efficacy and require refined treatment approaches.